Hörmann, A., Hopfgartner, B., Köcher, T., Corcokovic, M., Krammer, T., Reiser, C., Bader, G., Shi, J., Ehrenhöfer, K., Wöhrle, S., Schweifer, N., Vakoc, C. R., Kraut, N., Pearson, M., Petronczki, M., Neumüller, R. A.
(June 2018)
RIOK1 kinase activity is required for cell survival irrespective of MTAP status.
Oncotarget, 9 (47).
pp. 28625-28637.
ISSN 1949-2553
Abstract
Genotype specific vulnerabilities of cancer cells constitute a promising strategy for the development of new therapeutics. Deletions of non-essential genes in tumors can generate unique vulnerabilities which could be exploited therapeutically. The MTAP gene is recurrently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. Recent studies have uncovered an increased dependency of MTAP-deleted cancer cells on the function of a PRMT5 containing complex, including WDR77, PRMT5 and the kinase RIOK1. As RIOK1 kinase activity constitutes a potential therapeutic target, we wanted to test if MTAP deletion confers increased sensitivity to RIOK1 inhibition. Using CRISPR/Cas9-mediated genome engineering we generated analog sensitive alleles of RIOK1 in isogenic cell lines differing only by MTAP status. While we were able to independently confirm an increased dependency of MTAP-deleted cells on PRMT5, we did not detect a differential requirement for RIOK1 kinase activity between MTAP-proficient and deficient cells. Our results reveal that the kinase activity of RIOK1 is required for the survival of cancer cell lines irrespective of their MTAP status and cast doubt on the therapeutic exploitability of RIOK1 in the context of MTAP-deleted cancers.
| Item Type: |
Paper
|
| Additional Information: |
1949-2553
Hörmann, Alexandra
Hopfgartner, Barbara
Köcher, Thomas
Corcokovic, Maja
Krammer, Teresa
Reiser, Christoph
Bader, Gerd
Shi, Junwei
Ehrenhöfer, Katharina
Wöhrle, Simon
Schweifer, Norbert
Vakoc, Christopher R
Kraut, Norbert
Pearson, Mark
Petronczki, Mark
Neumüller, Ralph A
P01 CA013106/CA/NCI NIH HHS/United States
R01 CA174793/CA/NCI NIH HHS/United States
R01 GM045436/GM/NIGMS NIH HHS/United States
Journal Article
Oncotarget. 2018 Jun 19;9(47):28625-28637. doi: 10.18632/oncotarget.25586. eCollection 2018 Jun 19. |
| Uncontrolled Keywords: |
Mtap
Prmt5
Riok1
cancer
target |
| Subjects: |
bioinformatics
diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
Investigative techniques and equipment
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
Investigative techniques and equipment > CRISPR-Cas9
diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types |
| CSHL Authors: |
|
| Communities: |
CSHL labs > Vakoc lab
CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: |
Matthew Dunn
|
| Date: |
19 June 2018 |
| Date Deposited: |
10 Dec 2020 21:25 |
| Last Modified: |
20 Feb 2024 20:48 |
| PMCID: |
PMC6033344 |
| Related URLs: |
|
| URI: |
https://repository.cshl.edu/id/eprint/39705 |
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